Dehydroep:androsterone sailcylate useful against skin atrophy

ABSTRACT

Disclosed is the use of dehydroepiandrosterone salicylate in the treatment of skin atrophy. ##STR1## Such types skin atrophy to be treated include the thinning and/or general degradation of the dermis often characterized by a decrease in collagen and/or elastin as well as decreased number, size and doubling potential of fibroblast cells.

1. FIELD OF THE INVENTION

This invention relates to novel steroid esters useful for regulatingskin atrophy and other skin maladies, to pharmaceutical or cosmeticcompositions containing such steroid esters and to methods for theiruse.

2. BACKGROUND OF THE INVENTION

Dehydroepiandrosterone (DHEA) having the formula: ##STR2## and itssulfate ester (DHEAS) are secretory products of the human adrenalcortex. Both DHEA and DHEAS circulate in the blood stream at levels thatvary with age in adult men and women. For example, blood plasma levelsof DHEAS have been show to decrease fairly rapidly from a high level innewborns, then peak again in early advancing age (see, Orentreich, etal., J. Clin. Endocrinol. Metab., 59(3), 551 (1984).

DHEA has been used to treat a variety of ailments. U.S. Pat. No.4,628,052 to Peat teaches the use of DHEA and other steroids fortreating arthritis and non-specific joint pain. InternationalPublication WO 93/21771 to Daynes, et al. teaches the use of DHEA toreduce abnormally elevated interleukin 6 levels to treat individualswith rheumatoid arthritis, bacterial meningitis, alcoholic livercirrhosis, AIDS, and other pathologic conditions, as well as to treatburn victims and surgery patients.

DHEA has also been used to alleviate skin ailments. U.S. Pat. No.4,496,556 to Orentreich teaches the use of DHEA and fatty acid estersthereof, including DHEA acetate, DHEA valerate and DHEA enanthate totreat dry skin. Japanese Patent Application 60-161912 to Ogawa et al.,teaches cosmetic compositions containing a water-soluble DHEA salt totreat chapped skin. German patent No. DE 2147309 teaches the use of DHEAto treat psoriasis.

Non-steroid molecules, such as hydroxybenzoic acids andα-hydroxycarboxylic acids have also been used to treat skin conditions.α-Hydroxycarboxylic acids have been used to treat ichthyosis,hyperkeratoses, dandruff and ache (see, U.S. Pat. Nos. 3,879,537 to VanScott et al.; 3,920,835, 3,988,470, and 4,234,599 to Van Scott et al.;3,984,566 to Van Scott et al.; and 4,105,782 to Yu et al.;respectively). α-Hydroxycarboxylic acids have also been used to treatdry skin (see, U.S. Pat. Nos. 4,105,783 to Yu et al.; 4,194,007 to VanScott et al.; 4,197,316 to Yu et al.; 4,380,549 to Van Scott et al.;4,363,815 to Yu et al. and 4,091,171 to Yu et al. α-Hydroxycarboxylicacids have also been used to enhance the antiinflammatory action ofcorticosteroids (see, U.S. Pat. No. 4,246,261 to Van Scott et al.). U.S.Pat. No. 5,254,343 to Parah et el. discloses the use of salts ofα-hydroxyacids in conjunction with steroids to minimize cutaneousatrophy, a side-effect of steroid application to the skin.

One of the drawbacks of using α-hydroxyacids for treating skin ailmentsof a patient is that at high concentrations, α-hydroxyacids are known toremove the outer layer of skin by effectively burning the skin off thepatient. Such treatments are known in the art as "chemical peels."However, when improperly monitored, chemical peeling of the outer layerof skin using α-hydroxyacids can lead to inflammation, infection andscarring. Thus there is a need for a composition capable of providingthe skin-healing benefits of α-hydroxyacids while avoiding the drawbackssuch as those described above.

Salicylic acid has also been used to treat conditions of the skin.International Publication No. WO 93/10756, published Jun. 10, 1993 toBlank teaches the use of salicylic acid to regulate wrinkles and/oratrophy in mammalian skin. U.S. Pat. No. 5,262,407 to Leveque et al.teaches the use of C₁ -C₁₈ alkanoyl 5-acylsalicylic acids to treat agingskin.

One of the drawbacks associated with the use of DHEA in the treatment ofskin is that the increased sebum production resulting from suchtreatment is accompanied by or associated with the formation ofacne-like skin lesions in people who have a genetic tendency for acne.U.S. Pat. No. 4,542,129 to Orentreich teaches the use of a mixture ofDHEA and a keratolytic agent, such as a hydroxybenzoic acid or anα-hydroxycarboxylic acid, to treat dry skin while deterring acheformation.

Thus, there is a need for a composition with skin healing properties ofDHEA but that does not have the DHEA disadvantages. Similarly, there isa need for compounds having the advantageous properties ofα-hydroxycarboxylic acids that can function more effectively withsteroid compounds and without the deleterious effects of conventionalα-hydroxyacids.

Moreover, when compositions comprising more than one agent useful fortreating skin are intended to be formulated, solvents or vehicles whichsuccessfully dissolve or suspend one of the necessary agents may becompletely ineffective in dissolving or suspending the other(s), andvice versa. This can result in an excessive amount of time, energy andmanpower required for determining the proper formulation solvents orvehicles. Thus, there remains a need for such a composition which can bemore efficiently formulated.

It is an object of the present invention to provide novel compounds withenhanced skin-healing properties. It is a further object to providecompounds which have the advantages of DHEA and keratolytic agentswithout the above-mentioned biological disadvantages or formulationproblems.

3. SUMMARY OF THE INVENTION

The present invention provides novel steroid esters useful in regulatingskin atrophy and other skin maladies, compositions containing thesteroid esters and methods for their use.

Thus, the invention encompasses asteroid ester having the formula:##STR3## and pharmaceutically or cosmetically acceptable salts thereof,wherein,

R is A--CH(OH)--C(O)-- or (HO)C₆ H₄ C(O)--; and

A is hydrogen or a C₁ -C₂₂ alkyl or alkenyl group, said C₁ -C₂₂ alkyl oralkenyl group being optionally substituted with one or more C₁ -C₄ alkylgroups, phenyls, halogens or hydroxyl groups, said phenyl beingoptionally substituted with one or more halogens, hydroxyl groups ormethoxyl group, useful in regulating skin atrophy.

In a preferred embodiment of the invention, R is selected from the groupconsisting of 2-hydroxyethanoyl; 2-hydroxypropanoyl;2-methyl-2-hydroxypropanoyl; 2-hydroxybutanoyl; 2-hydroxypentanoyl;2-hydroxynonanoyl; 2-hydroxydecanoyl; 2-hydroxyoctanoyl;2-hydroxydodecanoyl; 2-hydroxytetradecanoyl; 2-hydroxyhexadecanoyl;2-hydroxyoctadecanoyl; 2-hydroxyeicosanoyl;2-hydroxyphenyl-2-hydroxyethanoyl; 2,2-diphenyl-2-hydroxyethanoyl;3-phenyl-2-hydroxypropanoyl; 2-phenyl-2-methyl-2-hydroxyethanoyl;2-(4'-chlorophenyl)-2-hydroxyethanoyl;2-(4'-hydroxy-3'methoxyphenyl)-2-hydroxyethanoyl;3-(2'-hydroxyphenyl)-2-hydroxypropanoyl;3-(4'-hydroxyphenyl)-2-hydroxypropanoyl;2-(3',4'-dihydroxyphenyl)-2-hydroxyethanoyl; and salicylyl. A preferredcompound of this invention is ##STR4## and pharmaceutically orcosmetically acceptable salts thereof.

In further embodiments, the invention encompasses cosmetic orpharmaceutical compositions containing one or more compounds of formulaII or a pharmaceutically or cosmetically acceptable salt thereof, and apharmaceutically or cosmetically acceptable carrier or excipient.

In a still further embodiment, the invention encompasses methods forregulating skin atrophy comprising administering to a subject a safe andeffective amount of one or more compounds of formula II, or apharmaceutically or cosmetically acceptable salt thereof, as describedabove.

In yet another embodiment, the invention encompasses methods forregulating skin atrophy comprising administering to a subject a safe andeffective amount of a composition comprising one or more compounds offormula II, or a pharmaceutically or cosmetically acceptable saltthereof and a pharmaceutically or cosmetically acceptable carrier orexcipient.

In yet another embodiment, the invention encompasses methods fortreating disorders including but not limited to dry skin, dandruff,acne, keratoses, psoriasis, eczema, pruritis, age spots, lentigines,melasmas, wrinkles (both coarse and fine, caused by intrinsic as well asextrinsic damage), warts, blemished skin, hyperpigmented skin,hyperkeratotic skin, inflammatory dermatoses, age-related skin changesand skin in need of cleansers.

The compounds of the present invention surprisingly demonstratepharmaceutical activity or cosmetic effects against skin disordersheretofore not achieved by DHEA itself or by the combination of DHEA andkeratolytic agents.

The present invention may be understood more fully by reference to thedetailed description and illustrative examples which are intended toexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1. DEFINITIONS

As used herein, "skin atrophy" means the thinning and/or generaldegradation of the dermis often characterized by a decrease in collagenand/or elastin as well as decreased number, size and doubling potentialof fibroblast cells. Skin atrophy is a natural result of aging. Skinatrophy may be caused by either intrinsic or extrinsic factors such asnatural chronoaging, photodamage, burns, or chemical damage. Skinatrophy is often an undesirable side effect resulting from treatmentwith corticosteroids.

As used herein, "regulating skin atrophy" means preventing, retarding,arresting, treating or reversing the process of atrophy in mammalianskin.

As used herein, "safe and effective amount" means an amount of compoundor composition sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The safe and effective amount of thecompound or composition will vary with the particular condition beingtreated, the age and physical condition of the patient being treated,the severity of the condition, the duration of the treatment, the natureof concurrent therapy, the specific compound, compounds or compositionemployed, the particular pharmaceutically-acceptable carrier utilized,and like factors within the knowledge and expertise of the attendingphysician or health care provider.

As used herein, "steroid ester" means any compound of formula II whereinthe hydroxyl group of DHEA is covalently bonded to a hydroxy-substitutedacyl or benzoyl moiety, forming an ester bond therewith.

As used herein, "cosmetic" means a formulation to be applied to the skinwhich improves the texture or appearance thereof, without necessarilyrendering a benefit or an effect of treating or preventing an abnormalbiological condition or a disease.

As used herein, "pharmaceutical" means a formulation to be applied tothe skin which renders a benefit or an effect of treating or preventingan abnormal biological condition or a disease.

As used herein, "eq." means a molar equivalent relative to the limitingreagent in the reaction mixture.

4.2. SYNTHESIS

The compounds of the present invention can be synthesized in accordancewith standard organic chemical techniques using readily/commerciallyavailable starting materials. Examples of the synthesis of suchcompounds are described below in Scheme 1. ##STR5##

Scheme 1

Steroid alcohol 1 can be obtained commercially from the Aldrich ChemicalCo., isolated from the human adrenal cortex, or synthesized byconventional organic synthesis.

The steroid alcohol 1 may be esterified with either anα-hydroxycarboxylic acid of the formula A--CH(OH)CO₂ H or ahydroxybenzoic acid of the formula (HO)C₆ H₄ CO₂ H, wherein A ishydrogen or a C₁ -C₂₂ alkyl or alkenyl group optionally substituted withone or more C₁ -C₄ alkyl groups, phenyls, halogens or hydroxyl groups,said phenyl being optionally substituted with one or more halogens,hydroxyl groups or methoxyl groups. Optionally, the steroid alcohol 1may be esterified with a protected α-hydroxy acid having the formulaA--CH(OP)CO₂ H or a protected hydroxybenzoic acid of the formula (PO)C₆H₄ CO₂ H, wherein A is defined as above and P is a suitable protectinggroup which allows the steroid hydroxyl to participate in anesterification reaction with the carboxyl group of either protected orunprotected carboxylic acid without interference from the unprotectedhydroxyl group. It is to be understood that the (HO) or (PO) moiety ofthe compound of formula 3 is "ortho" relative to the carboxyl group.Suitable protecting groups are those which may be removed subsequent tothe esterification reaction with steroid alcohol 1 without resulting incleavage of the newly formed ester bond. Examples of such protectinggroups may be found in T. D. Greene, Protecting Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981. Where A is optionallysubstituted with one or more hydroxyl groups, one or more of thosehydroxyl groups may be optionally protected with a suitable protectinggroup as defined above.

Steroid alcohol 1 is heated with either the protected or unprotectedcarboxylic acids, optionally in the presence of an acid catalyst, toobtain esters 2 or 3, respectively. Such an esterification proceeds withconcomitant loss of water. Suitable acid catalysts which can be usedinclude, but are not limited to hydrochloric acid, sulfuric acid,p-toluene sulfonic acid, methanesulfonic acid and other such acidcatalysts known to those skilled in the art. In this case, theprotecting group (P) should be stable to acidic conditions.

Alternatively, the protected or unprotected carboxylic acids may beconverted to their respective alkyl ester derivatives, preferably methylester derivatives, prior to esterification via means recited above. Thealkyl esters are prepared by heating the protected or unprotectedcarboxylic acids in a desired alkanol, preferably methanol, in thepresence of an acid catalyst recited above. Purification via standardmeans such as distillation, column chromatography, or recrystallizationaffords the desired alkyl ester derivative.

The esterification of steroid alcohol 1 with either A--CH(OH)CO₂ H,A--CH(OP)CO₂ H, (HO)C₆ H₄ CO₂ H or (PO)C₆ H₄ CO₂ H, or an alkylesterderivative thereof, is preferably conducted in the presence of areaction solvent including, but not limited to methylene chloride,chloroform, carbon tetrachloride, benzene, toluene, xylenes,tetrahydrofuran, diethyl ether, other suitable solvents known to thoseskilled in the art, and mixtures thereof. Preferably, the reactionsolvent is toluene.

The protected or unprotected carboxylic acids may also be converted totheir acid halide derivatives, preferably acid chloride derivatives,prior to esterification with 1. Preferably, the carboxylic acid isprotected. The protected or unprotected carboxylic acids may be treatedwith either thionyl chloride or oxallyl chloride to give thecorresponding acid chlorides, which may then react with 1 to give esters2 and 3 respectively. Such an esterification is generally performed inan organic solvent including, but not limited to methylene chloride,chloroform, carbon tetrachloride, benzene, toluene, xylenes,tetrahydrofuran, diethyl ether, other aprotic organic solvents known tothose skilled in the art, and mixtures thereof. The esterification ispreferably performed in the presence of a base including, but notlimited to triethylamine, disopropylethylamine, pyridine,4-dimethylaminopyridine, other bases known to those skilled in the art,and mixtures thereof. If 1 and the protected or unprotected carboxylicacids are soluble in the base, the organic solvent may optionally beomitted.

In addition, steroid alcohol 1 may be esterified by either the protectedor unprotected carboxylic acids in the presence ofdicyclohexylcarbodiimide. Preferably, a protected carboxylic acid isused. Such a reaction is generally performed in an organic solvent asdescribed above.

After the esterification of 1 with either A--CH(OP)CO₂ H or POC₆ H₄ CO₂H, the protecting group is removed to give esters 2 or 3, respectively.Methods for removing the protecting group can be found in T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1981.

The compound of formula III (DHEA salicylate) can be synthesizedaccording to two routes shown below.

In the first route (Scheme 2), DHEA is transesterified with an alkylsalicylate to give DHEA salicylate. Such alkyl salicylates contemplatedby the present invention are C₁ -C₅ alkyl salicylates. Preferably, thealkyl salicylate is methyl salicylate. An excess of either reactant,preferably an excess of alkyl salicylate, is used to effecttransesterification. DHEA and the alkyl salicylate, preferably methylsalicylate, are heated together, optionally in the presence of asuitable solvent such as those described above or known by those ofordinary skill in the art to facilitate such transesterificationreactions, at temperatures ranging from about 25° C. to about 120° C.,preferably from about 45° C. to about 85° C., to give DHEA and analkanol. It will be understood by those of ordinary skill in the artthat the alkanol obtained as a byproduct of transesterificationcorresponds to the alkyl salicylate employed in the transesterificationreaction. If methyl salicylate is used, the alkanol is methanol. Thealkanol byproduct may be distilled away from the reaction mixture, whichfurther drives the reaction to completion.

In addition, the transesterification reaction may optionally proceed inthe presence of a suitable catalyst. Suitable catalysts can be eitheracid catalysts or base catalysts. Such acid catalysts include, but arenot limited to, hydrochloric acid, sulfuric acid, p-toluenesulonic acid,methanesulfonic acid, and other acid catalysts known to those skilled inthe art. Such base catalysts include, but are not limited to the alkalimetal hydroxides, alkaline earth hydroxides, alkoxide salts such astitanium isopropoxide and others known to those skilled in the art.

The DHEA salicylate product may optionally be purified by methods suchas recrystallization or column chromatography. Such purification may beused to remove from the reaction mixture unwanted byproducts oftransesterification, such as, for example, salicylsalicylic acid ordisalicylide, and unreacted starting material. ##STR6##

In the second route (Scheme 3), salicylic acid, optionally anO-protected derivative thereof, is treated with an acid halide-formingreagent such as thionyl chloride or oxallyl chloride to give a salicylylhalide, or if an O-protected derivative of salicylic acid is used, anO-protected salicylyl halide, which reacts with DHEA to give DHEAsalicylate or if an O-protected derivative of salicylyl chloride isused, O-protected DHEA. Suitable O-protecting groups useful forprotecting the hydroxyl group of salicylic acid are found in T. W.Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, NewYork, 1981. Preferably, the acid halide-forming reagent is thionylchloride and the salicylyl halide is salicylyl chloride. The reactionmay optionally be performed in an aprotic solvent such as methylenechloride, chloroform, carbontetrachloride, tetrahydrofuran, 1,4-dioxane,benzene, toluene, xylenes, hexane, or preferably, cyclohexane.Preferably, a reaction catalyst, such as dimethylformamide, is added tothe mixture. If a reaction solvent is used, the mixture of reactionsolvent, salicylic acid or its O-protected derivative, and acidhalide-forming reagent, preferably in the presence of a reactioncatalyst, is heated from about 25° C. to reflux temperatures from about1 hour to approximately overnight, preferably from about 1 hour to aboutseveral hours.

The reaction mixture is then concentrated, optionally in vacuo, toafford acid chloride product, which can be used without furtherpurification or optionally purified via recrystallization prior to use.

Alternatively, the reaction mixture is diluted with an aprotic solvent,such as any of those listed above, to provide a solution containing theacid chloride product. If salicylic acid is used in the acidchloride-forming reaction, the above solution may also containsalicylsalicylic acid, disalicylide, or other salicylic acid-derivedbyproducts formed during the reaction between salicylic acid and theacid halide-forming reagent.

The crude or purified acid chloride product, or the solution containingthe acid chloride product is then combined with DHEA, optionally asolution of DHEA in an aprotic solvent, such as any of those listedabove, to give DHEA salicylate, or if an O-protected derivative ofsalicylyl chloride is used in the reaction, and O-protected derivativeof DHEA. The esterification can proceed at temperatures ranging fromabout -78° C. to 150° C., preferably from about 0° C. to about 100° C.and most preferably from about 25° C. to about 85° C. The esterificationreaction can optionally proceed in the presence of a base such astriethylamine, diisopropyl ethyl amine, pyridine,4-dimethylaminopyridine, or mixtures thereof. If base is added to thereaction mixture, it may be present in the amount of 0.01-10 eq.,preferably 0.01-2 eq. relative to the limiting reagent (i.e., either theDHEA or salicylyl halide which is not used in excess).

The reaction mixture, which contains the DHEA salicylate product or itsO-protected derivative and optionally salicylsalicylic acid,disalicylide or other salicylic acid-derived byproducts, is purified bystandard techniques, such as recrystallization or column chromatography,to give substantially pure DHEA salicylate or its O-protectedderivative. Removal of the O-protecting group of O-protected DHEAprovides DHEA. Methods for the removal of the chosen O-protecting groupare found in T. W. Greene, Protecting Groups in Organic Synthesis, JohnWiley & Sons, New York, 1981. ##STR7##

4.3. COMPOSITIONS

The compositions of the present invention can be used to treat skinatrophy and other disorders including but not limited to dry skin,dandruff, acne, keratoses, psoriasis, eczema, pruritis, age spots,lentigines, melasmas, wrinkles (both coarse and fine, caused byintrinsic as well as extrinsic damage), warts, blemished skin,hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers.

In regulating skin atrophy or other skin disorders as described above,compositions containing 0.005-50 wt. %, preferably 0.01-25 wt. % andmost preferably 0.01-5 wt. % of the steroid ester can be employed. Itshould be understood that two or more steroid esters of the presentinvention can be used in combination such that the combined weight % ofthose esters used in the above-mentioned compositions is within thoseranges mentioned above. Such compositions are preferably to be appliedtopically, so as to minimize systemic effects or undesirable sideeffects. The novel compounds may also be employed in pharmaceuticalcompositions suitable for parenteral (including subcutaneous,transdermal, intramuscular and intravenous) administration, although themost suitable route in any case will depend on the nature and severityof the condition being treated. The most preferred mode ofadministration for treating skin disorders, in particular skin atrophyor the skin disorders described above, is topical. In addition, thenovel compounds of the present invention may be further employed incosmetic compositions. In such an instance, the preferred mode ofadministration for treating skin disorders, in particular skin atrophy,is topical.

The compounds of the present invention can be formulated into suitablecosmetic or pharmaceutical compositions depending on the particular usefor which it is to be intended, for example, cosmetic or therapeutic, orboth. The cosmetic compositions can comprise one or more of the steroidesters of formula II and a pharmaceutically or dermatologicallyacceptable carrier or excipient.

The compositions of the present invention useful for topical applicationmay contain additional ingredients such as carrier, excipient or vehicleingredients such as, for example, water, acetone, ethanol, ethyleneglycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to form lotions,tinctures, creams, emulsions, gels or ointments which are non-toxic andpharmaceutically or dermatologically acceptable. Additionally,moisturizers or humectants can be added to the present compositions ifdesired. Examples of such additional ingredients can be found inRemington's Pharmaceutical Sciences, Eighteenth Edition, A. R. Gennaro,Ed., Mack Publishing Co., Easton, Pa., 1990.

In addition to these and other vehicles which will be obvious to thoseof ordinary skill in the art, it will be understood that thepharmaceutical or cosmetic compositions of the present invention mayinclude other ingredients such as those that improve or eradicate agespots, keratoses and wrinkles; analgesics; anesthetics; antiacne agents;antibacterials; antiyeast agents; antifungal agents; antiviral agents;antidandruff agents; antidermatitis agents; antipruritic agents;antiemetics; antimotion sickness agents; antiinflammatory agents;antihyperkeratolytic agents; antidryskin agents; antiperspirants;antipsoriatic agents; antieborrheic agents; hair conditioners and hairtreatment agents; antiaging antiwrinkle agents; antiasthmatic agents andbronchodilators; sunscreen agents; antihistamine agents; skin lighteningagents; depigmenting agents; vitamins; corticosteroids; tanning agents;hormones; retinoids; topical cardiovascular agents; clotrimazole;ketoconazole; miconazole; griseofulvin; hydroxyzine; diphenhydramine;pramoxine; lidocaine; procaine; mepivacaine; monobenzone; erythidocaine;procaine; mepivacaine; monobenzone; erythromycin; tetracycline;clindamycin; meclocyline; hydroquinone; minocycline; naproxen;ibuprofen; theophylline; cromolyn; albuterol; retinoic acid; 13-cisretinoic acid; hydrocortisone; hydrocortisone 21-acetate;hydro-cortisone 17-valerate; hydrocortisone 17-butyrate; betamethasonevalerate; betamethasone dipropionate; triamcinolone acetonide;fluocinonide; clobetasol propionate; benzoyl peroxide; crotamiton;propranolol; promethazine; vitamin A palmitate; vitamin E acetate andmixtures thereof.

The compounds of the present invention can be used as theirpharmaceutically or cosmetically acceptable salts. Such salts include,but are not limited to, sodium, potassium, lithium, calcium, magnesium,iron and zinc salts.

4.4. METHODS FOR REGULATING SKIN ATROPHY

The present invention also relates to a method for regulating skinatrophy or other skin disorders including but not limited to dry skin,dandruff, acne, keratoses, psoriasis, eczema, pruritis, age spots,lentigines, melasmas, wrinkles (both coarse and fine, caused byintrinsic as well as extrinsic damage), warts, blemished skin,hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers. Such a methodcomprises applying to the skin a safe and effective amount of one ormore of the novel steroid esters of the present invention. While thepresent invention relates to novel steroid esters used to treat skindisorders, the present invention further relates to the use ofcompositions, such as those discussed above, comprising one or more ofsaid steroid esters, to be used for treating skin disorders. The amountof steroid ester and frequency of treatment will vary widely dependingupon the level of skin atrophy already in existence in the subject (ifsuch exists), the rate of further atrophy, and the level of regulationdesired.

A preferred method of treating the skin is via chronic topicalapplication of a safe and effective amount of the steroid ester toregulate skin atrophy to treat other skin maladies described above. Theamount of steroid ester and frequency of topical application to the skincan vary widely, depending upon the particular skin disorder and theseverity thereof. It is well within the purview of the skilled artisan,such as a dermatologist or other health care provider, to regulatedosages according to patient needs. It is suggested as an example thattopical application range from about once per week to about 4 or 5 timesdaily, preferably from about 3 times a week to about 3 times daily, mostpreferably about once or twice per day. The composition for topicalapplication will comprise from about 0.005% to about 50%, preferablyfrom about 0.01% to about 25%, most preferably from about 0.01% to about5% of the active compound or mixture of compounds. By "chronic"application, it is meant herein that the period of topical applicationmay be over the lifetime of the patient, preferably for a period of atleast about one month, more preferably from about three months to abouttwenty years, more preferably from about six months to about ten years,more preferably still from about one year to about five years, therebyresulting in regulation of skin atrophy or other skin maladies describedabove.

A further preferred method of treating the skin is via occasionaltopical application of a safe and effective amount of the steroid esterfor cosmetic use. Such cosmetic uses include but are not limited tomoisturizing skin; masking skin blemishes or other undesired attributes;highlighting the skin as, for example, an eye shadow; improving skintexture; and the like. The amount of steroid ester and frequency oftopical application to the skin can vary widely, depending upondesirability of use. The composition for topical application willcomprise from about 0.005% to about 50%, preferably from about 0.01% toabout 25%, most preferably from about 0.01% to about 5% of the activecompound or mixture of compounds.

In another embodiment of the invention, regulating skin atrophy ortreating other skin maladies described above involves applying both asafe and effective amount of the steroid ester(s) and a safe andeffective amount of one or more of a sunscreening agent, ananti-inflammatory agent, an anti-oxidant/radical scavenging agent, achelating agent, a retinoid and/or a benzofuran derivative to the skinsimultaneously. As used herein, "simultaneous application" or"simultaneously" means applying the agents to the skin at the same situson the body at about the same time. Though this can be accomplished byapplying the agents separately to the skin, preferably a compositioncomprising all the desired agents commingled is applied to the skin. Theamount of sunscreening agent applied is generally from about 0.02 mg toabout 1.0 mg per cm² skin. The amount of anti-inflammatory agent appliedis generally from about 0.005 mg to about 0.5 mg, preferably from about0.01 mg to about 0.1 mg per cm² skin. The amount of chelating agentgenerally applied is from about 0.001 mg to about 1.0 mg, preferablyfrom about 0.01 mg to about 0.5 mg, more preferably from about 0.05 mgto about 0.1 mg per cm² skin. The amount of retinoid applied isgenerally from bout 0.00001 mg to about 0.02 mg per cm² skin. The amountof benzofuran derivative applied is generally from about 0.001 mg toabout 1.0 mg/cm² skin per application, preferably from about 0.01 toabout 0.5 mg/cm² skin per application. The amount of steroid ester(s)applied is generally from about 0.001 mg to about 1.0 mg per cm² skinper application, preferably from about 0.01 mg to about 0.5 mg per cm²,more preferably from about 0.05 to about 0.25 mg/cm² skin perapplication, which may vary upon the severity of the condition to betreated and the efficacy of the compounds employed.

The following specific, non-limiting examples concern the synthesis ofthe steroid esters of the instant invention and the preparation of atopical lotion, topical cream, topical ointment and topical gel usingvehicles previously used in other preparations. The formulations forthese preparations are given below in Table 1.

EXAMPLE NO. 1a

Dehydroepiandrosteryl Salicylate (DHEA Salicylate). To 100 g of DHEA in500 ml of methylene chloride are added 1.2 eq. of pyridine followed by1.1 eq. of 2-acetoxybenzoyl chloride and catalytic4-dimethylaminopyridine. The reaction is heated at 80° C. for 2 h. Aftercooling to room temperature, the reaction mixture is washed with 1N HClto remove excessive pyridine, and the organic phase is dried (MgSO₄),filtered and concentrated in vacuo. The residue is dissolved inmethanol/water and treated with excess sodium bicarbonate to give thetitle compound.

EXAMPLE NO. 1b

Dehydroepiandrosteryl Salicylate (DHEA Salicylate). To a reaction vesselfitted with a distillation head is added 100 g of DHEA, 5.0 eq of methylsalicylate and 0.01-0.05 eq. of p-toluenesulfonic acid. The reactionmixture is heated at 80°-100° C. until methanol ceases to distill off.The remaining methyl salicylate is removed via distillation underreduced pressure. The residue is purified via recrystallization or clumnchromatography to afford the title compound.

EXAMPLE NO. 2

Butylene glycol and water are mixed and dissolved in alcohol. Theresultant vehicle mixture and DHEA salicylate of Example No. 1 are mixedand dissolved. The resultant formulation is a tincture.

EXAMPLE NO. 3

In this example a topical cream is prepared by first mixing and meltingsqualane, stearyl alcohol NF, cetyl alcohol polyethylene glycol cetylether, mineral oil NF and petrolatum USP, at 70° C. A second mixture isformed by mixing and dissolving methyl paraben NF and propyl paraben NFin water, at 70° C. The second mixture is slowly added to and mixed withthe first mixture to form an emulsion. DHEA salicylate of Example No. 1is dispersed in the resultant emulsion at 50° C. The resultantcomposition is slowly cooled with mixing until the composition reachesroom temperatures.

EXAMPLE NO. 4

In this example a topical ointment is prepared. As a first step,glyceryl monostearate is mixed and melted in petrolatum USP at 70° C. Asa second step, DHEA salicylate of Example No. 1 is mixed and dissolvedin butylene glycol at 70° C. The resultant composition of step 2 isslowly added to the resultant composition of step 1, with mixing. Thismixture is then cooled to its congealing point with mixing and thencooled to room temperature without mixing.

EXAMPLE NO. 5

In this example a topical gel is prepared. As a first step, hydroxypropyl cellulose is hydrated and dissolved into water. As a second step,DHEA salicylate of Example No. 1, butylene glycol and PPG-12-Buteth-16are dissolved in alcohol. Slowly the resultant mixture of step 2 isadded into the resultant mixture of step 1 with mixing until a gelforms.

                                      TABLE 1                                     __________________________________________________________________________    Steroid Ester Formulations                                                                    Example No. 2                                                                         Example No. 3                                                                         Example No. 4                                                                         Example No. 5                                         Topical Topical Topical Topical                                               Tincture                                                                              Cream/Lotion                                                                          Ointment                                                                              Gel                                   Ingredients     % w/w   % w/w   % w/w   % w/w                                 __________________________________________________________________________     1.                                                                              Steroid ester of formula I                                                                 1.0     1.0     1.0     1.0                                      or DHEA Salicylate                                                          2.                                                                              Methyl Paraben NF    .01                                                    3.                                                                              Propyl Paraben NF    .01                                                    4.                                                                              Hydroxy Propyl Cellulose             1.0                                      (note 1)                                                                    5.                                                                              PPG-12-Buteth-16 (note 2)            2.0                                    6.                                                                              Squalane (note 3)    2.0                                                    7.                                                                              Glyceryl Monostearate NF     2.0                                            8.                                                                              Stearyl Alcohol NF   2.8                                                    9.                                                                              Cetyl Alcohol NF     4.2                                                   10.                                                                              Polyethylene Glycol  5.0                                                      Cetyl Ether (note 4)                                                          Mineral Oil NF       5.0                                                      Butylene Glycol                                                                            4.0             12.0    4.0                                      Petrolatum USP       5.4     85.0                                             Alcohol (note 5)                                                                           89.0                    47.0                                     Water        6.0     74.4            45.0                                                  100.0   100.0   100.0   100.0                                 __________________________________________________________________________     Notes:                                                                        (1) available under the trademark Klucel ® from Hercules                  (2) available under the trademark Ucon ® fluid 50 HB from Union           Carbide                                                                       (3) available under the trademark Robane ® from Robeco                    (4) available under the trademark Brij 58 ® from ICI                      (5) contains 95% ethanol and 5% water                                    

EXAMPLE NO. 6

To examine the effect of the steroid esters of the present invention onstratum corneum, stratum corneum samples are first equilibrated to 44%relative humidity (RH) by suspending the samples over a saturated saltsolution of potassium carbonate. After equilibration, the stratumcorneum samples are extended by 2% of their original length at 20 mm/minusing a linear extensometer. The amount of force required to extend thesample is computed and the information displayed as a force extensiongraph on a personal computer. The initial slope of the curve in theHookean region is then used as an indicator of the integrity of thestratum corneum (gram-force/100% extension). 50 μl of the steroid esterto be tested is then applied to the external surface of five pieces ofstratum corneum samples and rubbed in with 20 strokes of a glovedfinger. The samples are then equilibrated to 80% RH by suspending over asaturated salt solution of ammonium sulfate in humidity chambers andthen incubated at this humidity for three hours. The samples are thenreequilibrated to 44% RH and after conditioning, restretched to 2%extension. Results are then expressed as extensibility ratios ofbefore/after treatment. The same test is run for 4% extension.

EXAMPLE NO. 7

To the half an area of the face, neck, forearm, back or buttocks of eachmember of a panel of approximately 50 healthy volunteers is applied acomposition comprising 0.01-5 wt. % of asteroid ester or mixture ofsteroid esters of the present invention and to the other half an area isapplied a control composition. Applications are made once to 4 timesdaily for up to six months or more depending upon the condition to betreated. Panelists are assessed by expert assessors for overallimprovement in the condition to be treated or the look and feel of theskin.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

A number of references have been cited and the entire disclosures ofwhich are incorporated herein by reference.

What is claimed is:
 1. A method for regulating skin atrophy in a patientwhich comprises topically administering to the area of atrophied skin ofthe patient a composition comprising a pharmaceutically or cosmeticallyacceptable vehicle and a compound having the structure ##STR8## or apharmaceutically or cosmetically acceptable salt thereof.
 2. The methodof claim 1 wherein said compound is present in an amount of about 0.01-5wt. % of the composition.
 3. The method of claim 1 wherein said vehicleis selected from the group consisting of lotions, tinctures, creams,emulsions, gels and ointments.